A convenient synthesis of novel pyridazino[3,4-b]quinoxalines

Novel 4-chlorophenylhydrazono-3-oxo-1,2,3,4-tetrahydropyridazino[3,4-b]quinoxalines 10a-c were synthesized by the cyclization of the α-hydrazonohydrazides 8a-c. The chlorination of 10a with phosphoryl chloride afforded 3-chloro-4-[2-(o-chlorophenyl)hydrazino]pyridazino[3,4-b]quinoxaline 12.     

Synthesis of pyridazino[3,4-b]quinoxalines and pyrazolo[3,4-b]-quinoxaline by 1,3-dipolar cycloaddition reaction

The pyridazino[3,4-b]quinoxalines 6a,b and pyrazolo[3,4-b]quinoxaline hydrochloride 9 were synthesized by the 1,3-dipolar cycloaddition reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with dimethyl or diethyl acetylenedicarboxylate and 2-chloroacrylonitrile, respectively. The reaction mechanisms were postulated for the formation of 6a,b and 9 .     

Synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline and related compounds

This paper describes the synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline ( 10 ), tetrazolo[4,3-b]pyridazino[4,5-b]quinoxaline ( 11 ) and some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 . Starting with 2-ethoxycarbonyl-3-methylquinoxaline 1,4-dioxide ( 1 ), 1,2-dihydro-1-oxopyridazino[4,5-b]quinoxaline ( 5 ) was prepared by three different ways: (a) chlorination of 1 in acetic acid gave 2-ethoxycarbonyl-3-dichloromethylquinoxaline 1,4-dioxide, which reacts with an excess of hydrazine to give about 60% of 5 ; (b) oxidation of 1 with selenium dioxide gave 90% of 2-ethoxycarbonyl-3-formylquinoxaline 1,4-dioxide ( 3 ), which reacts with hydrazine to give 5 (63%); (c) compound 3 was treated with hydrazine to give 1,2-dihydro-1-oxopyridazino-[4,5-b]quinoxaline 1,4-dioxide ( 4 ) (70%), which by reduction with sodium dithionite gave 5 (80%). Compound 5 reacts with phosphorus pentasulfide or the Lawesson reagent to give 1,2-dihydro-1-thiocarbonylpyridazino[4,5-b]quinoxaline ( 9 ), which treated with hydrazine gave 5 (80%). This last compound reacts with nitrous acid to give 11 . Some hydrazones 12 from 10 are described. Heating the aldehyde hydrazones 12a,c,d with dimethylsulfoxide some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 were obtained. Compound 13a was also obtained in the reaction of 10 with benzoyl chloride. Reaction of 3 with phenylhydrazine gave 1,2-dihydro-1-oxo-2-phenylpyridazino[4,5-b]quinoxaline ( 6 ). Reactions of 5 with acetic anhydride and dimethylsulfate gave, respectively, 1-acetoxypyridazino[4,5-b]quinoxaline ( 8 ) and 1,2-dihydro-1-oxo-2-methylpyridazino-[4,5-b]quinoxaline ( 7 ). All the compounds were characterized by elemental analysis and ¹H-nmr spectra. Compounds 5 and 10 showed antihypertensive activity in rats.     

Pyridazino[3,4-b]quinoxalines and their reduced derivatives. Preparation and structure

The reaction of o-phenylenediamine with a β-ketoacid, leads in most cases to quinoxalinones. Their structure has been determined as well as that of their corresponding hydrazones. The reaction of hydrazine with these quinoxalinones gives dihydropyridazino[3,4-b]quinoxalines, the structure of which has been ascertained. It has been shown that among the six possible formulas, the only 1,2-dihydro structure fits with the spectroscopic data. On the contrary, N-substituted o-phenylenediamines lead to 2,10-dihydro derivatives. The electrochemical behavior of the 2,10-dihydro-10-methyl-3-phenylpyridazino[3,4-b]quinoxaline has been investigated. It has also been shown that the 3,4,6-trichloropyridazine reacts with o-phenylenediamines to give 5,10-dihydropyridazino[3,4-b]quinoxalines. These compounds can be oxidized to give the new heterocycle pyridazino[3,4-b]quinoxaline.     

The chemistry of 1,2,5-thiadiazoles V. Synthesis of 3,4-diamino-1,2,5-thiadiazole and [1,2,5] thiadiazolo[3,4-b]pyrazines

The o-diamine, 3,4-diamino-1,2,5-thiadiazole ( 2 ), was synthesized from 3,4-dichloro-1,2,5-thiadiazole ( 3 ) hy three methods. Aqueous glyoxal cyclized 2 into [1,2,5]thiadiazolo[3,4–6]-pyrazine ( 14 ). 3,4-Dichloro-1,2,5-thiadiazole 1,1-dioxide ( 18 ) reaeted with 2 to give 1,3-dihydro-bis[1,2,5]thiadiazolo[3,4-b:3′,4′-e]pyrazine 2,2-dioxide ( 19 ). The reaction of 2 with selenium oxyehloride led to [1,2,5]selenadiazolo[3,4-c] [1,2,5]thiadiazole ( 12 ). Ring closure of 2,3-diaminoquinoxaline ( 4 ) with thionyl chloride or selenium oxychloride gave [1,2,5]thiadiazolo-[3,4-b]quinoxaline ( 21 ) and [1,2,5]selenadiazolo[3,4-b]quinoxaline ( 22 ), respectively. Sulfurous acid reduced 21 to the 4,9-dihydro derivative 23 , which was reoxidized to 21 with chloranil. Aqueous hase hydrolyzed 21 to 4 via the hydrated intermediate 24 . Aqueous glyoxal cyclized 4 to the covalent hydrate of pyrazino[2,3-b]quinoxaline ( 26 ), 27 , which was dehydrated to 26 . Compound 26 underwent rapid addition of two alcohols in a process analogous to covalent hydration.     

Benzo[f]isoindole analogs II. Thieno[3,4-b]quinoxaline

The transient existence of thieno[3,4-b]quinoxaline ( 2d ) as a product of dehydration of 1,3-dihydrothieno[3,4-b]quinoxaline 2-oxide ( 5 ) was demonstrated by trapping experiments with N-phenylmaleimide and dimethyl acetylenedicarboxylate. Attempts to isolate 2d from reaction mixtures arising from dehydration of 5 and from dehydrogenation of 1,3-dihydro-thieno[3,4-b]quinoxaline ( 8 ) were unsuccessful.     

Synthesis of biologically active pyridazinoquinoxalines

The 2‐(1‐methylhydrazino)quinoxaline 4‐oxides 9a,b were converted into the pyridazino[3,4‐b]‐quinoxalines 10a,b,15a,b,22 and 1,2‐diazepino[3,4‐b]quinoxalines 29a‐c , which were further transformed into the 3‐substituted 1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones 5–8 .     

The syntheses of pyridazino[1,2-a] pyridazine derivatives of furan,pyridazine and pyrrole by diels-alder reactions

Diels-Alder adducts were formed in the lead tetraacetate oxidations of substituted cyclic hydrazides of furan, pyridazine and pyrrole dicarboxylic acids in the presence of 1,3-cyclo-hexadiene or 1,3-cyclopentadiene. The products resulting were furo[3,4-g]pyridazino[1,2-a]-pyridazine-6,10-diones, pyridazino[4,5-g]pyridazino[1,2-a]pyridazine-6,11-diones, and pyrrolo-[3,4-g]pyridazino[1,2-a]pyridazine-6,10-diones, respectively. Some hydrogenations and ring opening reactions were studied.     

Preparation of novel tricyclic ring systems containing the pyridazinone ring

Novel tricyclic ring systems, irmdazo[3,4-d]pyridazino[4,5-b][1,4]thiazines 3 , imidazo[2,1-b]pyridazino[4,5-e][1,3,4]thiadiazines 15 and 18 were prepared by the reaction of 5-amino-4-chloropyridazin-3(2H)-ones 1 and 5(4)-(1-methylhydrazino)-4(5)-chloropyridazin-3(2H)-ones 13 (16) with isothiocyanates 2 and 7 .     

Reactions of furoxano[3,4-b]quinoxaline with alkynes and alkenes. Synthesis of pyrazino[2,3-b]quinoxaline 1,4-dioxides

Pyrazino[2,3-b]quinoxaline 1,4-dioxides 3a-e were prepared by reacting Furoxano[3,4-b]quinoxaline with alkynes and alkenes.     

A new synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines via a Key Intermediate

The chlorination of the α-hydrazonoester 4 with phosphoryl chloride/pyridine gave 3-[α-(o-chlorophenylhydrazono)methoxycarbonylmethyl]-2-chloroquinoxaline 5 , whose cyclization with 1,8-diazabicyclo[5,4,0]-7-undecene afforded 3-methoxycarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 6 . The reaction of 6 with hydrazine hydrate provided 3-hydrazinocarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 7 , whose reactions with methyl and allyl isothiocyanates furnished 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 2 and 3-(4-allyl-2,3-dihydro-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chloropheny)-1H-pyrazolo[3,4-b]quinoxaline 8 , respectively. Moreover, the reactions of 7 with triethyl orthoformate and orthoacetate gave 1-(o-chlorophenyl)-3-(1,3,4-oxadiazol-5-yl)-1H-pyrazolo-[3,4-b]quinoxaline 9a and 1(o-chlorophenyl)-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 9b , respectively.     

3-Amino-2-quinoxalinecarbonitrile. New fused quinoxalines with potential cytotoxic activity

Starting with 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide 1 , a new series of quinoxaline derivatives was prepared through chemical modifications of the 2-cyano and 3-amino groups. Nitration of 3-amino-2-quin-oxalinecarbonitrile 3 afforded the 7-nitro derivative 6 . Diazotation of 3 gave the 3-chloro compound 9 . 2,3-Quinoxalinedicarbonitrile 14 was obtained from 9 . Pyridazino[4,5-b]quinoxalines 15 and 16 were prepared by condensing 14 with hydrazine hydrate. A triazolo[4,5-b]quinoxaline 18 , a isothiazolo[4,5-b]quinoxaline 20 and two pyrazolo[3,4-b]quinoxalines 21 and 22 were identified. Compounds were tested as cytotoxic agents both in oxic and in hypoxic cells.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.     

Synthesis of some new derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole

This paper describes the synthesis of 1-chloro-4-hydrazino-5H-pyridazino[4,5-b]indole ( 4 ) and some of the triazoles ( 6–8 ), tetrazoles ( 10–11 ), triazolotetrazoles ( 9 ) and bis-tetrazoles ( 12 ) derived from it. All of these were previously unknown compounds. Treating 1,4-dioxo-1,2,3,4-tetrahydro-5H-pyridazino[4,5-b]indole ( 1 ) with phosphorus oxychloride gave 1,4-dichloro-5H-pyridazino[4,5-b]indole ( 2 ), which reacts regioselectively with hydrazine to give compound 4 . The reactions of 4 with formic and acetic acids gave 6-chloro-11 H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles ( 6a-6b ), respectively. Reaction of compound 6a with hydrazine gave 6-hydrazino-11H-1,2,4-triazolo[4,3–6]-pyridazino[4,5,-b]indole ( 8 ). This with nitrous acid gave 6-azido-11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]-indole ( 9 ). Compound 4 reacted with nitrous acid to give 6-chloro-11H-tetrazolo[4,5-b]pyridazino[4,5-b]-indole ( 10 ), which gave 1,4-diazydo-5H-pyridazino[4,5-b]indole ( 12 ), through successive reactions with hydrazine and nitrous acid. All compounds were characterized by elemental analysis, ir and ¹H-nmr spectra.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

A convenient synthesis of 5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines utilizing a 1,3-dipolar cycloaddition reaction and an intramolecular alcoholysis

The reaction of the hydrazones 5a-c with 2-chloroacrylonitrile produced the 1,2-diazepino[3,4-b]quinoxaline hydrochlorides 6a-c , which were transformed into the 5,6,7,13-tetrahydro-5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines 7a-c , respectively. The oxidation of 7a-c with diethyl azodicarboxylate afforded the 7,13-dihydro-5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines 8a-c , respectively. Compounds 7a-c and 8a-c were also obtained by a one-pot synthesis from 5a-c and 6a-c , respectively.     

Synthesis and biological activities of quinolone analogues: Pyridazino[3,4‐b]quinoxalin‐4‐one

Quinolone analogues I‐VI with pyridazino[3,4‐b]quinoxaline ring system were synthesized form the (l‐alkylhydrzino)quinoxalina N‐oxides 1 via oxidation of pyridazino[3,4‐b]quinoxalines 2,3,5,7 , quinoxalino[2,3‐c]cinnolines 4 , and 1,2‐dizepino[3,4‐b]quinoxalines 6 . The biological activities of quinolone analogues IVa (N₁‐methyl‐C₃‐methyl), Va (N₁‐methyl‐C₃‐ethyl), and VI (N₁‐methyl‐C₃‐H) were superior to those of quinolone analogues I (N₁‐ethyl‐C₃‐carboxyl), 26b (N₁‐ethyl‐C₃‐carboxylate), and IIIc,d [N₁‐alkyl‐C₃‐(CH₂)₃COOC₂H₅].     

Quinolone analogues 6 [1‐5]. Synthesis of 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones

The reaction of the quinoxaline N‐oxides 7a,b with diethyl ethoxymethylenemalonate gave the 1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 8a,b , whose reaction with N‐bromosuccinimide or N‐chlorosuccinimide afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4,4‐dicarboxylates 9a‐d. The reaction of compounds 9a‐d with hydrazine hydrate resulted in hydrolysis and decarboxylation to provide the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 10a‐d , whose reaction with nitrous acid effected oxidation to furnish the 3‐halogeno‐4‐hydroxy‐1‐methylpyridazino[3,4‐b]quinoxaline‐4‐carboxylates 11a‐d , respectively. The reaction of compounds 11a‐d with hydrazine hydrate afforded the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4‐ols 12a‐d , whose oxidation provided the 3‐halogeno‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐ones 6a‐d , respectively. Compounds 6a‐d had antifungal activities in vitro.     

A convenient synthesis of 1,2,4-triazolo[4,3,2-o,p]-[1,3]diazocino[4,5-b]quinoxalines via a 1,3-dipolar cycloaddition reaction and a ring transformation

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 5 with triethyl orthoformate gave 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 6. The reaction of compound 6 with phenyl isocyanate afforded 7-chloro-4-phenylamino-1,2,4-triazolo[4,3-a]quinoxaline 7 , while the reaction of compound 6 with phenyl isothiocyanate resulted in deoxygenation to provide 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 8. However, the reaction of compound 6 with allyl isothiocyanate effected the 1,3-dipolar cycloaddition reaction, but not deoxygenation, to furnish 9-chloro-4,5-dihydroisoxazolo[2,3-a][1,2,4]triazolo[3,4-c]quinoxalin-5-ylmethylisothiocyanate 9. Moreover, the reduction of compound 9 with iron/acetic acid resulted in ring transformation to give 11 -chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2- o,p][1,3]diazocino[4,5-b]quinoxaline 10 , whose acetylation afforded 5-acetyl-11-chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2-o,p][1,3]diazocino[4,5-b]quinoxaline 11.